1. GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms.
- Author
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Ludwig, Nataniel Floriano, Velho, Renata Voltolini, Sperb-Ludwig, Fernanda, Acosta, Angelina Xavier, Ribeiro, Erlane Marques, Kim, Chong A., Gandelman Horovitz, Dafne Dain, Boy, Raquel, Rodovalho-Doriqui, Maria Juliana, Lourenço, Charles Marques, Santos, Emerson Santana, Braulke, Thomas, Pohl, Sandra, and Schwartz, Ida Vanessa D.
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LYSOSOMAL storage diseases , *DNA mutational analysis , *PHOSPHOTRANSFERASES , *ENDOPLASMIC reticulum , *GENOTYPES , *GENETICS - Abstract
Mucolipidoses (ML) II and III alpha/beta are lysosomal storage diseases caused by pathogenic mutations in GNPTAB encoding the α⁄β-subunit precursor of GlcNAc-1-phosphotransferase. To determine genotype-phenotype correlation and functional analysis of mutant GlcNAc-1-phosphotransferase, 13 Brazilian patients clinically and biochemical diagnosed for MLII or III alpha/beta were studied. By sequencing of genomic GNPTAB of the MLII and MLIII alpha/beta patients we identified six novel mutations: p.D76G, p.S385L, p.Q278K fs *3, p.H588Q fs *27, p.N642L fs *10 and p.Y1111*. Expression analysis by western blotting and immunofluorescence microscopy revealed that the mutant α⁄β-subunit precursor p.D76G is retained in the endoplasmic reticulum whereas the mutant p.S385L is correctly transported to the cis -Golgi apparatus and proteolytically processed. Both mutations lead to complete loss of GlcNAc-1-phosphotransferase activity, consistent with the severe clinical MLII phenotype of the patients. Our study expands the genotypic spectrum of MLII and provides novel insights into structural requirements to ensure GlcNAc-1-phosphotransferase activity. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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